This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.
International Patent Application WO 87/06576, which was published on Nov. 5, 1987, refers to 5-(3-[(2-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, and states that it is useful as an antidepressant. International Patent Application WO 91/07178, which was published on May 30, 1991, refers to the utility of this compound in the treatment of asthma, inflammatory airway diseases and skin diseases.
U.S. Pat. No. 5,270,206, which issued on Dec. 14, 1993, refers to a process for preparing (+)-(2R)-endo-norborneol (also referred to as (2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S, 2R, 4R)-bicyclo[2.2.1]heptan-2-ol) and (xe2x88x92)-(2S)-endo-norborneol (also referred to as (2S)-endo-bicyclo[2.2.1]heptan-2-ol or (1R, 2S, 4S)-bicyclo[2.2.1]heptan-2-ol), and to their further conversion into the pharmaceutically active agents 5-(3-[(2S)-exo-bicyclo[2.2.1)]hept-2-yloxy]4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, depicted below, 
and 5-(3-[(2R)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, depicted below, 
All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties.
This invention relates to a compound having the formula 
wherein X and Y are the same and are selected from xe2x80x94CN, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2 and xe2x80x94CONHOH, or X and Y, taken together, form a group of the formula 
This invention also relates to a compound having the formula 
wherein R1 and R2 are independently selected from (C1-C6) alkyl and hydrogen.
This invention also relates to compounds of the formulae 
wherein each R2 is independently selected from (C1-C6) alkyl.
This invention also relates to a process for preparing a compound of the formula 
wherein X and Y are the same and are selected from xe2x80x94CN, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2 and xe2x80x94CONHOH, or X and Y, taken together, form a group of the formula 
comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is defined as above, in the presence of a base, preferably a tertiary amine, to yield a compound of the formula II wherein X and Y are both xe2x80x94CN, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2 or xe2x80x94CONHOH; or (2) (a) reacting a compound of the formula II wherein X and Y are both xe2x80x94CN with hydrogen peroxide, preferably basic aqueous hydrogen peroxide, to form the corresponding bis-amide in which both xe2x80x94CN groups are replaced by xe2x80x94CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base (e.g., an alkali metal alkoxide containing from one to six carbon atoms or an alkali metal hydroxide), to form a cyclic urea wherein X and Y, taken together, form a group of the formula xe2x80x9caxe2x80x9d, as depicted above.
This invention also relates to a process for preparing a compound of the formula 
wherein X and Y are defined as for formula II above, comprising reacting a compound of formula II, as defined above, with, respectively, R-(+)-endo-norborneol or S-(xe2x88x92)-endo-norborneol, a triaryl or trialkyl phosphine and an azo dicarboxylate.
This invention also relates to a process for preparing a compound of the formula 
wherein X and Y are the same and are selected from xe2x80x94CN, xe2x80x94CONH2, CO2(C1-C6)alkyl and xe2x80x94CONHOH, or X and Y, taken together, form a group of the formula 
comprising: (1) reacting 3-hydroxy4-methoxybenzaldehyde with a compound of the formula XCH2CO2H, wherein X is xe2x80x94CN, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2 or xe2x80x94CONHOH, in the presence of a base, preferably a tertiary amine, to form a compound of the formula 
wherein X and Y are the same and are selected from xe2x80x94CN, xe2x80x94CONH2, xe2x80x94CO(C1-C6)alkyl and xe2x80x94CONHOH; or (2) (a) reacting a compound of the formula II wherein X and Y are both xe2x80x94CN with hydrogen peroxide to form the corresponding bis-amide in which both xe2x80x94CN groups are replaced by xe2x80x94CONH2; (b) subjecting the bis-amide formed in step (a) to a Hoffman rearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) to form the corresponding biscarbamate; and (c) reacting the biscarbamate formed in step (b) with a base (e.g., an alkali metal alkoxide containing from one to six carbon atoms), to form a cyclic area wherein X and Y, taken together, form a group of the formula 
and then (3) reacting said compound of formula II so formed in step 1 or 2 above with, respectively, R-(+)-endo-norborneol or S-(xe2x88x92)-endo-norborneol, a triaryl or trialkyl phosphine and an azo dicarboxylate.
This invention also relates to a process for preparing a compound of the formula 
wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl, comprising reacting, respectively, a compound of the formula 
with diacetoxyiodobenzene, NaOZ and Zxe2x80x2OH, wherein Z and Zxe2x80x2 are independently selected from hydrogen and (C1-C6)alkyl.
This invention also relates to a process for preparing a compound of the formula 
comprising reacting, respectively, a compound of the formula 
wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl with compounds of the formulae NaOZ and Zxe2x80x2OH, wherein Z and Zxe2x80x2 are independently selected from hydrogen and (C1-C6)alkyl.
This invention also relates to a process for preparing a compound of the formula 
comprising:
reacting, respectively, a compound of the formula 
with diacetoxyiodobenzene, NaOZ and Zxe2x80x2OH, wherein Z and Zxe2x80x2 are independently selected from hydrogen and (C1-C6)alkyl, to form an intermediate of the formula 
wherein R1 and R2 are independently selected from hydrogen and (C1-C6)alkyl; and then either
(b1) isolating said intermediate of formula V or Vxe2x80x2 and reacting it with compounds of the formulae NaOZ and Zxe2x80x2OH, wherein Z and Zxe2x80x2 are defined as above; or
(b2) reacting said intermediate of formula V or Vxe2x80x2 in situ with compounds of the formula NaOZ and Zxe2x80x2OH, wherein Z and Zxe2x80x2 are defined as above.
As used herein, the expression xe2x80x9creaction inert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product or products.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
Formulae II, and V and Vxe2x80x2 above include compounds identical to those depicted but for the fact that one or more hydrogen, carbon, nitrogen or oxygen atoms are replaced by radioactive or stable isotopes thereof. Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
The processes of the this invention and methods of preparing the novel compounds of this invention are described in the following reaction schemes and discussion. Unless otherwise indicated, the substituents X, Y, R, R1, R2, R3, and R4, group xe2x80x9c(a)xe2x80x9d and formulae II, III, IIIxe2x80x2, IV, IVxe2x80x2, V, Vxe2x80x2, VI and VIxe2x80x2 in the reaction schemes and discussion that follow are defined as above. 
Scheme 1 illustrates the preparation of compounds of the formulae II and III. Scheme 2 illustrates the preparation of compounds of the formula V and also the preparation of 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2-(1H)-one (compound VI) from the compound of formula III wherein X and Y are both xe2x80x94CN. (Such compound of formula III wherein X and Y are both xe2x80x94CN is referred to in scheme 2 and hereinafter as the compound of formula IIIA.) Scheme 3 illustrates the preparation of compound VI from compounds of the formula III wherein X and Y are both xe2x80x94CO2(C1-C6)alkyl or xe2x80x94CONHOH. (The compound of formula III wherein X and Y are both xe2x80x94CO2(C1-C6)alkyl or xe2x80x94CONHOH are referred to in scheme 3 and hereinafter, respectively, as the compound of formula IIIB or IIIC).
Referring to scheme 1, isovanillin (compound I) is condensed with two molar equivalents of a compound of the formula XCH2CO2H, wherein X is xe2x80x94CN, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2 or xe2x80x94CONHOH, in a sequential Knoevenagel-Michael sense with accompanying decarboxylation, to yield a compound of the formula II, wherein X and Y are the same and are selected from the values given in the above definition of X, in a reaction inert solvent in the presence of a base, preferably a tertiary amine. This reaction may be conducted at a temperature ranging from about 10xc2x0 C. to about 130xc2x0 C. It is preferably conducted at about the reflux temperature. Suitable solvents include but are not limited to N-methylmorpholine, triethylamine, pyridine, as well as non-basic reaction-inert solvents such as tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile and toluene. Preferably, a secondary amine (e.g., piperidine or pyrrolidine) is also added as a catalyst. In one preferred embodiment of the reaction, N-methylmorpholine is used as the solvent/base and piperidine is also added to the reaction mixture.
Compounds of the formula II wherein X and Y, taken together, form a group of the xe2x80x9caxe2x80x9d (i.e., the cyclic urea) may be prepared by subjecting the compound of formula II wherein X and Y are both xe2x80x94CN to the series of reactions illustrated in scheme 2 and described later in this application.
The compound of formula II formed in the above reaction can be converted into the corresponding compound of the formula III by coupling it under Mitsunobu conditions with either R-(+)-endo-norborneol, depicted below, 
or S-endo-norborneol, depicted below 
to yield, respectively, the corresponding compound of formula III or IIIxe2x80x2 having the opposite stereochemistry as determined by the endo-norborneol reactant. Thus, if R-endo-norborneol is used, the product will be a compound of the formula III that has an xe2x80x9cSxe2x80x9d configuration, and if S-endo-norborneol is used, the product will be a compound of the formula IIIxe2x80x2 that has an xe2x80x9cRxe2x80x9d configuration.
This reaction is typically carried out in the presence of a triaryl or trialkyl phosphine such as triphenylphosphine or tributylphosphine and an azo dicarboxylate oxidizing agent. It is also generally carried out in an aprotic solvent such as tetrahydrofuran (THF) acetonitrile, methylene chloride, DMF, toluene and benzene, preferably THF, at a temperature from about 10xc2x0 C. to about 150xc2x0 C., preferably at about the reflux temperature. Suitable azo compounds include diisopropylazodicarboxylate, azodicarbonyldipiperidine and diethylazodicarboxylate. Diisopropylazodicarboxylate and azodicarbonyldipiperidine are preferred.
The stereochemistry of the compound of formula III or IIIxe2x80x2 formed in the above step is retained in all subsequent steps shown in schemes 2 and 3.
As indicated above, scheme 2 illustrates the conversion of compounds of the formula IIIA into compounds of the formula VI. Referring to scheme 2, a compound of the formula IIIA is hydrolyzed with hydrogen peroxide, preferably basic aqueous hydrogen peroxide, to form the bis-amide of formula IV. This reaction is typically conducted in a polar solvent such as acetone, ethanol, isopropanol or methyl ethyl ketone, with acetone being preferred, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., with about room temperature being preferred. Sodium carbonate or another inorganic salt of similar basicity may be added to the reaction mixture to accelerate the reaction.
The compound of formula IV so formed is then subjected to a Hoffman rearrangement reaction in which both carboxamide groups are converted, with migration of nitrogen, into the carbamate groups of formula V. Suitable oxidizing reagents include bis(acetoxy)iodobenzene, bis(trifluoroacetoxy)iodobenzene, NaOCl, NaOBr and lead tetracetate may be used. Bis(acetoxy)iodobenzene is preferred. This reaction is typically carried out in the presence of a base. When diacetoxyiodobenzene is used, acceptable bases include alkali metal hydroxides and (C1-C6)alkoxides. The reaction temperature may range from about xe2x88x9220xc2x0 C. to about 100xc2x0 C., with from about 0xc2x0 C. to about 25xc2x0 C. being preferred. Examples of appropriate reaction-inert solvents are (C1-C6)alkanols, THF, DMF and acetonitrile.
The final step in the sequence is the base catalyzed closure of the biscarbamate of formula V to form the symmetrical pyrimidin-2-one of formula VI. This reaction may be carried out from about 0xc2x0 C. to about 100xc2x0 C., and is preferably carried out at the reflux temperature. Suitable solvents include but are not limited to lower alcohols, with methanol being preferred. Suitable bases include alkali metal alkoxides containing from one to six carbon atoms. The preferred base is sodium methoxide.
Alternatively, the last two steps of the sequence may be accomplished in a combined fashion without the isolation of the bis-carbamate V. This modification is essentially identical to the previous description of the Hoffman rearrangement. It is preferable to conduct the reaction at the reflux temperature of the solvent. It is also preferable to add additional base to the reaction mixture. The range of acceptable oxidizing agents, bases and solvents is the same as described previously. The preferred reaction utilizes diacetoxyiodobenzene, sodium methoxide and methanol.
The reaction of compounds of the formula V to form compounds of the formula VI, as described above, may proceed through one or both of the intermediates of formulae VII and VII shown in scheme 2A.
The compound of formula III wherein X and Y are both xe2x80x94CONH2 is the same as the compound of formula IV, and therefore it can be converted into compound (VI) using the methods illustrated in scheme 2.
Compounds of the formula III wherein X and Y are both xe2x80x94CONHOH or xe2x80x94CO2(C1-C6)alkyl may be converted into compound VI using the methods illustrated in scheme 3.
Referring to scheme 3, the diester of formula IIIB is reacted with hydroxylamine hydrochloride in the presence of a base, e.g., a tertiary amine base, to form the hydroxamic acid of formula IIIC. This reaction can be conducted in a variety of reaction-inert solvents that do not have a strong nucleophilic character, including but not limited to lower alcohols, cyclic and acyclic ethers (e.g., ethyl ether or THF), neutral aromatic compounds such as benzene and toluene, DMF, dimethylacetamide, ethyl acetate, acetonitrile and water, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably at about 20xc2x0 C.
The hydroxamic acid of formula IIIC can then be converted into compound VI via a Loessen rearrangement using conditions or a reagent having the ability to dehydrate an alcohol, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably at about 20xc2x0 C. The preferred reagent is p-toluenesulfonylchloride. Alternatively, one can form a different ester of the hydroxamic acid, optionally in situ, and then convert that ester via heat and/or acid treatment into the compound of formula VI, using methods well known in the art.
The preparation of other compounds of the present invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in the scheme above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 3 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
The processes and products of this invention are useful in the synthesis of the pharmaceutically active compounds VI and VIxe2x80x2. Compounds VI and VIxe2x80x2, as well as racemic mixtures of these compounds (hereinafter referred to, collectively as xe2x80x9cthe active compoundsxe2x80x9d) are useful in the treatment of depression, asthma, inflammatory airway disorders and skin disorders (e.g., psoriasis and atopic dermatitis).
The active compounds are calcium independent c-AMP phosphodiesterase inhibitors. The ability of such compounds to inhibit c-AMP phosphodiesterase may be determined by the method of Davis, Biochimica et Biophysica. Acta., 797, 354-362 (1984).
The antidepressant activity of the active compounds may be determined by the behavioral despair paradigm described by Porsult et al., Arch. Int. Pharmacodyn., 227, 327-336 (1977) and by the procedure described by Roe et al., J. Pharmacol. Exp. Therap., 226, 686-700 (1983) for determining the ability of a test drug to counteract reserpine hypothermia in mice.
When used for the treatment of depression the active compounds are used as is or in the form of pharmaceutical compositions comprising an active compound and pharmaceutically-acceptable carriers or diluents. For oral administration, the preferred route for administering the active compounds, suitable pharmaceutical carriers include inert diluents or fillers, thereby forming dosage forms such as tablets, powders, capsules, and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For example, tablets containing various excipients, such as sodium citrate, are employed, together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. preferred materials therefor include lactose or milk sugar and high molecular weight polyethylene glycols.
For oral administration, the daily dose of active agent is from about 0.1 mg to about 10 mg, and for parenteral administration, preferably i.v. or i.m., from about 0.01 mg. to about 5 mg. The prescribing physician, of course, will ultimately determine the appropriate dose for a given human subject dependent upon factors such as the severity of the patient""s symptoms and the patient""s response to the particular drug.
In vitro and in vivo tests relevant to the utility of the active compounds in treating asthma and skin disorders are discussed in International Patent Application WO 91/07178, referred to above and incorporated herein by reference in its entirety, on pages 4 and 5 of the specification and in Examples 1-3.
In the systemic treatment of asthma or inflammatory skin diseases with one of the active compounds, the dosage is generally from about 0.01 to 2 mg/kg/day (0.5-100 mg/day in a typical human weighing 50 kg) in single or divided doses, regardless of the route of administration. Of course, depending upon the exact compound and the exact nature of the individual illness, doses outside this range will be prescribed at the discretion of the attending physician. In the treatment of asthma, intranasal (drops or spray), inhalation of an aerosol through the mouth, and conventional oral administration are generally preferred. However, if the patient is unable to swallow, or oral absorption is otherwise impaired, the preferred systemic route of administration will be parenteral (i.m., i.v.). In the treatment of inflammatory skin diseases, the preferred route of administration is oral or topical. In the treatment of inflammatory airway diseases, the preferred route of administration is intranasal or oral.
The active compounds are generally administered in the form of pharmaceutical compositions comprising one of said compounds together with a pharmaceutically acceptable vehicle or diluent. Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; for parenteral administration, in the form of injectable solutions or suspensions, and the like; for topical administration, in the form of solutions, lotions, ointments, salves and the like, in general containing from about 0.1 to 1% (w/v) of the active ingredient; and for intranasal or inhaler administration, generally as 0.1 to 1% (w/v) solution.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples.